Different brain functional network abnormalities between attention-deficit/hyperactivity disorder youth with and without familial risk for bipolar disorder.

Attention-deficit/hyperactivity disorder (ADHD) commonly precedes the initial onset of mania in youth with familial risk for bipolar disorder (BD). Although ADHD youth with and without BD familial risk exhibit different clinical features, associated neuropathophysiological mechanisms remain poorly understood. This study aimed to identify brain functional network abnormalities associated with ADHD in youth with and without familial risk for BD. Resting-state functional magnetic resonance imaging scans were acquired from 37 ADHD youth with a family history of BD (high-risk), 45 ADHD youth without a family history of BD (low-risk), and 32 healthy controls (HC). Individual whole-brain functional networks were constructed, and graph theory analysis was applied to estimate network topological metrics. Topological metrics, including network efficiency, small-worldness and nodal centrality, were compared across groups, and associations between topological metrics and clinical ratings were evaluated. Compared to HC, low-risk ADHD youth exhibited weaker global integration (i.e., decreased global efficiency and increased characteristic path length), while high-risk ADHD youth showed a disruption of localized network components with decreased frontoparietal and frontolimbic connectivity. Common topological deficits were observed in the medial superior frontal gyrus between low- and high-risk ADHD. Distinct network deficits were found in the inferior parietal lobule and corticostriatal circuitry. Associations between global topological metrics and externalizing symptoms differed significantly between the two ADHD groups. Different patterns of functional network topological abnormalities were found in high- as compared to low-risk ADHD, suggesting that ADHD in youth with BD familial risk may represent a phenotype that is different from ADHD alone.

Changes in the structural brain connectome over the course of a nonrandomized clinical trial for acute mania.

Disrupted topological organization of brain functional networks has been widely reported in bipolar disorder. However, the potential clinical implications of structural connectome abnormalities have not been systematically investigated. The present study included 109 unmedicated subjects with acute mania who were assigned to 8 weeks of treatment with quetiapine or lithium and 60 healthy controls. High resolution 3D-T1 weighted magnetic resonance images (MRI) were collected from both groups at baseline, week 1 and week 8. Brain networks were constructed based on the similarity of morphological features across brain regions and analyzed using graph theory approaches. At baseline, individuals with bipolar disorder illness showed significantly lower clustering coefficient (Cp) (p = 0.012) and normalized characteristic path length (λ) (p = 0.004) compared to healthy individuals, as well as differences in nodal centralities across multiple brain regions. No baseline or post-treatment differences were identified between drug treatment conditions, so change after treatment were considered in the combined treatment groups. Relative to healthy individuals, differences in Cp, λ and cingulate gyrus nodal centrality were significantly reduced with treatment; changes in these parameters correlated with changes in Young Mania Rating Scale scores. Baseline structural connectome matrices significantly differentiated responder and non-responder groups at 8 weeks with 74% accuracy. Global and nodal network alterations evident at baseline were normalized with treatment and these changes associated with symptomatic improvement. Further, baseline structural connectome matrices predicted treatment response. These findings suggest that structural connectome abnormalities are clinically significant and may be useful for predicting clinical outcome of treatment and tracking drug effects on brain anatomy in bipolar disorder. CLINICAL TRIALS REGISTRATION: Name: Functional and Neurochemical Brain Changes in First-episode Bipolar Mania Following Successful Treatment with Lithium or Quetiapine. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00609193. Name: Neurofunctional and Neurochemical Markers of Treatment Response in Bipolar Disorder. URL: https://clinicaltrials.gov/ . REGISTRATION NUMBER: NCT00608075.